Li L, Wang Z, Ma B, Ye Q, Lei Y, Lu M, Ye L, Kang J, Huang W, Xu S, Wang K, Chen Y, Liu J, Gao Y, Wang C, Ma J, Li L

NF-?B pathway dysregulation, a common driver of therapy resistance in cancer, promotes survival by suppressing apoptosis. While the anti-apoptotic role of NF-?B is recognized, the molecular mechanisms underlying this process remain poorly defined. Here, we identify the E3 ubiquitin ligase RNF25 as a key mediator of NF-?B-dependent apoptosis resistance in ...

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renal cell carcinoma cells, enabling evasion of multiple targeted therapies. Mechanistically, RNF25 binds TRIP4 and catalyzes its non-degradative ubiquitination at lysine 135, disrupting TRIP4-p65 interactions. This modification liberates p65 to activate NF-?B signaling, upregulating anti-apoptotic effectors (e.g., cIAP2, Bcl-2). We further demonstrate that the NF-?B inhibitor BAY11-7082 directly interacts with RNF25, reversing its pro-survival effects and restoring apoptosis sensitivity. Our findings establish RNF25 as a druggable orchestrator of therapy resistance through NF-?B pathway modulation and propose pharmacological targeting of RNF25 by BAY11-7082 as a strategy to overcome apoptosis resistance in renal malignancies.

Date: Aug. 06, 2025

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